title: IL-11 is required for A1 adenosine receptor-mediated protection against ischemic AKI.
abstract: A1 adenosine receptor activation ameliorates ischemic AKI through the induction of renal proximal tubular sphingosine kinase-1. However, systemic adverse effects may limit A1 adenosine receptor-based therapy for ischemic AKI, indicating a need to identify alternative therapeutic targets within this pathway. Here, we evaluated the function of renal proximal tubular IL-11, a clinically approved hematopoietic cytokine, in A1 adenosine receptor-mediated induction of sphingosine kinase-1 and renal protection. Treatment of human proximal tubule epithelial (HK-2) cells with a selective A1 adenosine receptor agonist, chloro-N(6)-cyclopentyladenosine (CCPA), induced the expression of IL-11 mRNA and protein in an extracellular signal-regulated kinase-dependent manner, and administration of CCPA in mice induced renal synthesis of IL-11. Pretreatment with CCPA protected against renal ischemia-reperfusion injury in wild-type mice, but not in IL-11 receptor-deficient mice. Administration of an IL-11-neutralizing antibody abolished the renal protection provided by CCPA. Similarly, CCPA did not induce renal IL-11 expression or protect against renal ischemia-reperfusion injury in mice lacking the renal proximal tubular A1 adenosine receptor. Finally, treatment with CCPA induced sphingosine kinase-1 in HK-2 cells and wild-type mice, but not in IL-11 receptor-deficient or renal proximal tubule A1 adenosine receptor-deficient mice. Taken together, these results suggest that induction of renal proximal tubule IL-11 is a critical intermediary in A1 adenosine receptor-mediated renal protection that warrants investigation as a novel therapeutic target for the treatment of ischemic AKI.
authors.affiliation: Department of Anesthesiology and.
authors.forename: Joo Yun
authors.initials: JY
authors.lastname: Kim
authors.forename: Mihwa
authors.initials: M
authors.lastname: Kim
authors.forename: Ahrom
authors.initials: A
authors.lastname: Ham
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
authors.forename: Robert W
authors.initials: RW
authors.lastname: Greene
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Lee
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000517:prevention & control*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002460:Cell Line; D006801:Humans; D017370:Interleukin-11 / Q000096:biosynthesis / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000502:physiology*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D017370:Interleukin-11; D043682:Receptor, Adenosine A1; C058394:2-chloro-N(6)cyclopentyladenosine; D000241:Adenosine